CROI 2016 Abstract eBook

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Poster Abstracts

Methods: This study included 423 seminal samples from 196 HIV+men from the San Diego Primary Infection Cohort. Levels of seminal HIV RNA and HHV DNA (cytomegalovirus [CMV], Epstein-Barr virus [EBV], herpes simplex virus 1 & 2 [HSV], HHV-6, -7 and -8) were measured by RT PCR. Longitudinal shedding rates were determined by survival analysis. Predictors of seminal HIV shedding were determined using backwards selection in a multivariable GEE model. Results: The first time-point was collected within a median estimated duration of infection (EDI) of 90 days (IQR: 75-166), and 99 individuals had additional time-points over a median follow-up of 119 days (IQR: 36-243). Overall 15% of time-points were sampled on ART and with suppressed plasma HIV RNA. Within the first 48 weeks of EDI, 94% of men had detectable seminal DNA from at least one HHV. Most commonly CMV (85%) and EBV (81%), followed by HHV-7 (35%), HHV-6 (29%), HHV-8 (26%) and HSV (23%). Overall, shedding of seminal HHV was not affected by CD4, HIV RNA, EDI and ART status but did decline with older age (p<0.05). Among shedders with longitudinal sampling (≥2 time- points), intermittent shedding patterns (changing shedding status) was less likely for CMV (17%) and EBV (36%) than for HHV-7 (47%), HHV-8 (50%), HHV-6 (60%) and HSV (67%). Seminal HIV RNA was detectable in 97% of men over the first 48 weeks of EDI and was significantly lower when plasma HIV RNA was undetectable (78% vs 33%, p<0.05). Presence of CMV, EBV and HSV (but not CD4, CD8, age and EDI) were independent predictors of seminal HIV shedding after adjusting for plasma HIV and longitudinal measurements. Odds ratios (OR) for associations with seminal HIV shedding were 9.0 (95% CI: 1.1-74.5) for HSV, 1.9 (1.0-3.5) for CMV, 1.9 (1.0-3.7) for EBV, and 2.2 (1.7-2.9) for each increment of log 10 viral load in plasma. Conclusions: Seminal HHV replication was prevalent in our HIV primary infection cohort and was not affected by clinical or demographic parameters with exception of age. Persistent CMV and EBV shedding was common and significantly associated with seminal HIV shedding. HSV shedding was less frequent and mostly intermittent in our cohort, but its association with seminal HIV shedding was the strongest. 728 HSV-2 Acquisition Among HIV-1 Infected Adults With Tenofovir-Based ART in ACTG 5175 Connie M. Celum 1 ;Ting Hong 1 ; Anne Cent 1 ; Rhoda Morrow 1 ; Jared M. Baeten 1 ; Nagalingeswaran Kumarasamy 2 ; Beatriz Grinsztejn 3 ; Mina Hosseinipour 4 ;Thomas B. Campbell 5 ; for the ACTG 5175 team 1 Univ of Washington, Seattle, WA, USA; 2 YRG Cntr for AIDS Rsr and Educ, Chennai, India; 3 Inst de Pesquisa Clínica Evandro Chagas (IPEC)/Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil; 4 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5 Univ of Colorado, Denver, CO, USA Background: HSV-2 infection is highly prevalent (50-90%) in HIV-infected persons and associated with increased HIV viral load and greater risk of transmission and disease progression. Tenofovir disoproxil fumarate (TDF) has in vitro efficacy against HSV-2 and reduced HSV-2 acquisition in HIV-1 uninfected persons on PrEP. A majority of HIV-infected persons are on TDF-containing antiretroviral treatment (ART); however, the efficacy of TDF to reduce HSV-2 acquisition in HIV-infected persons is unknown. Methods: ACTG 5175 (PEARLS) was an open label randomized trial, which enrolled 1571 ARV naïve HIV-infected persons from India, Brazil, Malawi, South Africa, USA, Peru, Zimbabwe, Haiti, and Thailand from 2005-07 and followed through 2010. Participants were randomized to receive a TDF-containing regimen (TDF, emtricitabine & efavirenz) or a non-TDF regimen (zidovudine, lamivuidine, & efavirenz or didanosine, emtricitabine, & atazanavir). We analyzed baseline and exit visit HSV-2 serostatus by Focus HSV-2 EIA with HSV Western blot to confirm indeterminate EIAs (0.9-3.4). An intent to treat analysis was conducted. Results: Of 1567 HIV-infected persons who initiated ART, 53%were male and 51%were <35 years of age; 525 were randomized to an ART regimen with TDF and 1042 to a regimen without TDF. 68 HSV-2 seroconversions occurred: 24 in persons randomized to the TDF regimen (6.4 HSV-2 incidence/100 person-years, p-yrs) and 44 were in persons randomized to a non-TDF regimen (6.6 HSV-2 incidence/100 p-yrs) with a hazard ratio (HR) of 0.89 (95% CI 0.55-1.44; p=0.63). Of 374 p-yrs in the TDF-containing arm, 9 p-yrs were in 27 persons who switched to a non-TDF regimen, and of 663 p-yrs among those randomized to a non-TDF regimen, 161 p-yrs were in 101 persons who switched to the TDF-containing regimen. The unadjusted HR among those who never switched was 1.34 (95% CI 0.7-2.58; p=0.38). Conclusions: In this international, multi-site open label trial of 3 ART regimens, annual HSV-2 incidence was high (average 6.5/100 p-yrs across arms) among HSV-2 uninfected, HIV-infected persons. There was no protective benefit of TDF against HSV-2 acquisition in the randomized comparison, although the high rate of switching to a TDF regimen among those randomized to a non-TDF regimen reduced the ability to detect an effect. Given that our findings conflict with the reduction in HSV-2 accquistion in HIV-uninfected persons on TDF PrEP, further research on whether TDF can prevent HSV-2 acquisition in HIV-infected persons is needed. 729 CMV Status Is AssociatedWith CD4/CD8 Restoration in Primary HIV-Infected Patients Patrick Miailhes 1 ; Christophe Malcus 1 ; Pierre Pradat 2 ; Isabelle Delfour 2 ; Julien Saison 2 ; Jean-ClaudeTardy 2 ; Isabelle Cohen-Codar 3 ; Christian Chidiac 2 ; Guillaume Monneret 1 ;Tristan Ferry 2 1 CHU Lyon, Lyon, France; 2 Hopital de la Croix Rousse, Lyon, France; 3 AbbVie Inc, Rungis, France Background: The objective was to identify factors associated with the normalization of the CD4/CD8 ratio (>=1) in patients with a history of primary HIV infection (PHI) and long- term combined antiretroviral therapy (cART). Methods: Cross-sectional study conducted in Lyon, France in HIV patients with a known history of PHI and a minimum of 2 years of effective cART (< 200 copies/ml) without interruption or virological failure. Baseline factors at the time of PHI, type and duration of first and total cART, CMV status, and level of activation markers on CD4 and CD8 cells (CD38 and HLA-DR) at the time of the study were assessed. Patients with hepatitis C or B virus co-infection or with a history of neoplasia or immunosupressive therapy after the date of PIH were excluded. Results: A total of 83 patients (87%males, median age 37 years [range 18-63]), 85%with a positive CMV serology) were studied. cART was initiated after a median of 10.2 months [0-198] after PHI. Twenty-nine (35%) began cART early within three months after diagnosis of PHI. Before cART, median CD4 nadir was 304 cells/µl [18-642] and viral load 212643 copies/ml [64-10 7 ]. The first cART included either a combination of nucleosides with protease inhibitor in 73% or a non-nucleoside analogue or three nucleosides in 27% of cases, respectively, with a similar median duration (13 months). Overall, patients had cART during a median of 7.3 years [2-18.9] with a median of three different lines of cART. Sixty-seven (81%) had more than 500 CD4/µl and 68% achieved a CD4/CD8 ratio >=1 at the time of the study. A CD4/CD8 ratio >=1 was significantly associated with a lower percentage of HLA-DR+ on CD4 and CD8 cells (9.7 vs 17.6%, p<0.0001 and 29.9 vs 39.7%, p=0.001, respectively). Conversely, age, gender, early initiation of active cART (< 3 months) and type of first cART, were not associated with better CD4/CD8 restoration. The seronegative CMV status was also significantly associated with a higher CD4/CD8 ratio (1.72 vs 1.11; p=0.009) and lower percentage of HLA-DR+ (p<0.001) and CD38+HLA-DR+ (p=0.020) on CD8 cells. Conclusions: In patients with a history of PHI and long-term active cART, a seronegative CMV status was strongly associated with a lower residual immune activation and a better restoration of the CD4/CD8 ratio. 730 CD4+ T Cell Dysfunction During Early HIV Infection Might Trigger CMV Shedding Jennifer M. Dan 1 ; Marta Massanella 2 ; Davey M. Smith 1 ; MilenkaVargas 1 ; Rachel Schrier 1 ; Susan J. Little 1 ; Sara Gianella 1 1 Univ of California San Diego, San Diego, CA, USA; 2 CRCHUM, Montreal, QC, Canada Background: Asymptomatic seminal cytomegalovirus (CMV) replication among ART-treated individuals is associated with increased CD4 + T-cell activation, proliferation and exhaustion as well as higher levels of HIV transcription and persistence. The interplay between persistent CMV replication and antigen-specific immune response (CMV and HIV) during early HIV-infection is unknown. Methods: Paired seminal and blood samples from 28 ART-naïve early HIV-infected CMV-seropositive men who have sex with men (15 CMV shedders and 13 non shedders) were evaluated. Levels of seminal CMV DNA and HIV RNA were measured by RT-PCR, and expression of intracellular interferon (IFN)-γ was measured by flow cytometry from peripheral blood mononuclear cells (PBMC) following overnight stimulation with whole CMV and HIV lysate. Levels of programmed death receptor-1 (PD-1) were measured on unstimulated PBMCs. Associations between immunological markers and asymptomatic CMV and HIV replication were determined using Mann-Whitney U tests.

Poster Abstracts

303

CROI 2016